氟伐他汀对幼兔动脉粥样硬化及血管LOX-1表达的早期干预作用

Early intervention on atherosclerosis by fluvastatin and lectin-like oxidized low-density lipoprotein receptor-1 expression in atherosclerotic arteries in immature rabbits

目的观察三羟基三甲基辅酶A(HMG-CoA)还原酶抑制剂——他汀类对幼兔动脉粥样硬化(AS)的防治作用并探讨其发挥作用的机制。方法通过高脂饮食建立幼兔AS模型,设对照组、高脂组、氟伐他汀(简称他汀)组,12周后检查外周血血脂指标;腹部血管超声检测腹主动脉内膜-中层厚度(aIMT);病理形态学观察腹主动脉组织学变化并进行病理形态学定量分析;逆转录-聚合酶链反应(RT-PCR)和免疫组化分别检测腹主动脉血管壁植物血凝素样氧化低密度脂蛋白受体1(LOX-1)的基因和蛋白表达。结果高脂饮食诱导幼兔高胆固醇血症(HC)及早期AS模型,外周血总胆固醇(TC)、低密度脂蛋白(LDL)升高;B超显示aIMT增厚;病理组织学显示内膜(I)/中层(M)厚度比值(I/M)、I+M、内膜/中层面积比值(SI/SM)增大,腹主动脉血管壁LOX-1基因与蛋白水平表达显著增强;他汀组血脂降低,aIMT、I/M、I+M以及SI/SM明显减小,同时氟伐他汀可显著抑制血管壁过度增强的LOX-1基因水平与蛋白水平的表达。结论他汀类药物早期应用可通过降低血脂显著抑制饮食诱导的幼兔HC和早期AS血管病变的发生、发展,并通过减少血管LOX-1的表达发挥内皮保护作用。

Objective The present study was designed to investigate the preventive and therapeutic effect of 3-hydroxy-3-methylglutanyl coenzyme A （HMG-CoA） reductase inhibitor fluvastatin on the development of atherosclerosis （ AS ） in immature rabbits and its possible mechanism by detecting the expression level of lectin-like oxidized low-density lipoprotein receptor-1 （ LOX-1 ） in the abdominal arota. Methods A model of hypercholesterolemia （HC） was established by high-cholesterol diet and 24 immature rabbits were divided randomly and equally into control group, HC-diet group and fluvastatin group. At the beginning of the study and after 12 weeks, the body height （BH） and body weight （BW） of the rabbits were measured and their body mass index （BMI） was calculated. At the end of 12 weeks, serum total cholesterol （TC） and low-density lipoprotein （LDL） levels were examined. The intima-medial thickness of the abdominal aorta （aIMT） was measured by using non-invasive high-resolution （ 14 MHz） B-mode ultrasound imaging. Histological changes in abdominal arteries were studied by H＆E-staining and histomorphometric analysis. The gene expression of LOX-1 in abdominal aorta was evaluated by semi-quantitative reverse transcription-polymerase chain reaction （RT-PCR） and its protein expression was examined by immunohistochemistry. Results High cholesterol diet induced hypercholesterolemia and early AS in immature rabbits. In HC-diet group serum TC and LDL levels in rabbits elevated. B mode echocardiography showed that aIMT was thickened and pathomorphology indicated that extensive aortic intima （I） and intima and media （I ＋ M） became thickened and the ratio of the area of intima to media （SI/SM ） was increased. Aortic intimal proliferation in HC-diet group was associated with a marked increase in LOX-1 expression （ protein and mRNA） in endothelium and neointima of the abdominal aorta. Treatment with fluvastatin at a dosage of 10 mg/（ kg · d） deduced serum lipid, attenuated artery intimal proliferation and markedly decreased the enhanced LOX-1 expression level in endothelium and neointima in immature rabbits. There were no significant differences of BH, BW or BMI among the three groups. Conclusions These findings suggested that early treatment with fluvastatin not only induced a significant regression of arterial lesions of HC and early AS in immature rabbits, but also had a crucial endothelial protective effect by down-regulating LOX-1 expression level in atherosclerotic arteries in early AS.